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The Antiprotozoal Drug Pentamidine Ameliorates Experimentally Induced

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The Antiprotozoal Drug Pentamidine Ameliorates Experimentally Induced Esposito et al. Journal of Neuroinflammation 2012, 9:277 JOURNAL OF http://www.jneuroinflammation.com/content/9/1/277 NEUROINFLAMMATION RESEARCH Open Access The antiprotozoal drug pentamidine ameliorates experimentally induced acute colitis in mice Giuseppe Esposito1*, Elena Capoccia1, Giovanni Sarnelli2, Caterina Scuderi1, Carla Cirillo2,3, Rosario Cuomo2 and Luca Steardo1 Abstract Background: Intestinal inflammation is partly driven by enteroglial-derived S100B protein. The antiprotozoal drug pentamidine directly blocks S100B activity. We aimed to investigate the effect of pentamidine on intestinal inflammation using an animal model of dextran sodium sulphate (DSS)-induced acute colitis. Methods: Mice were divided into: control group, colitis group (4% DSS for four days) and two pentamidine-treated colitis groups (0.8 mg/kg and 4 mg/kg). Anti-inflammatory effect of pentamidine was assessed in colonic tissue by evaluating the disease activity index and the severity of histological changes. Colonic tissue were also used to evaluate cyclooxigenase-2, inducible nitric oxide synthase, S100B, glial fibrillary acidic protein, phosphorylated-p38 MAPkinase, p50, p65 protein expression, malondyaldheyde production, mieloperoxidase activity, and macrophage infiltration. Nitric oxide, prostaglandin E2, interleukin-1 beta, tumor necrosis factor alpha, and S100B levels were detected in plasma samples. Parallel measurements were performed in vitro on dissected mucosa and longitudinal muscle myenteric plexus (LMMP) preparations after challenge with LPS + DSS or exogenous S100B protein in the presence or absence of pentamidine. Results: Pentamidine treatment significantly ameliorated the severity of acute colitis in mice, as showed by macroscopic evaluation and histological/biochemical assays in colonic tissues and in plasma. Pentamidine effect on inflammatory mediators was almost completely abrogated in dissected mucosa but not in LMMP. Conclusions: Pentamidine exerts a marked anti-inflammatory effect in a mice model of acute colitis, likely targeting S100B activity. Pentamidine might be an innovative molecule to broaden pharmacological tools against colitis. Keywords: Pentamidine, Acute colitis, S100B protein, Enteric glia Background and protective functions toward enteric neurons and are Although the etiology of ulcerative colitis (UC) remains fully implicated in the modulation of neuronal activities incompletely understood, severe and persistent mucosal [5]. Moreover, EGC have been repeatedly reported to trig- infiltration of macrophages and neutrophils in the large ger and support intestinal inflammation [6] and to function intestine represents a prominent feature [1]. Immune as a first line of defense against pathogens [7]. EGC may cells release cytokines, interleukins and proinflammatory proliferate and be activated in response to injury and in- signaling molecules [2-4]. In addition to the well-known flammation undergoing reactive gliosis (enterogliosis), a involvement of macrophages and neutrophils, other cell condition in which they release neurotrophins, growth fac- types have been recently reported to substantially con- tors and proinflammatory cytokines cross-talking with tribute to the onset and progression of the disease. En- other infiltrating immune cells [8]. Alterations in the teric glial cells (EGC) play a fundamental role in the homeostasis of the enteric nervous system are induced by maintenance of gut homeostasis since they have trophic reactive enterogliosis and are characterized by the massive overexpression and secretion of specific astroglial-derived signaling molecules such as S100B protein [9,10]. * Correspondence: [email protected] ++ ++ 1Department of Physiology and Pharmacology ‘Vittorio Erspamer’, University S100B is a diffusible, Ca /Zn -p53 binding protein SAPIENZA of Rome, P. le Aldo Moro 5, 00185, Rome, Italy playing a pivotal role during intestinal inflammation, Full list of author information is available at the end of the article © 2012 Esposito et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Esposito et al. Journal of Neuroinflammation 2012, 9:277 Page 2 of 12 http://www.jneuroinflammation.com/content/9/1/277 since it orchestrates proinflammatory signals [11,12]. Disease activity index (DAI) Aberrant expression and release of S100B correlate with The DAI scale is based on the evaluation of different the inflammatory status of the gut. S100B accumulates parameters characterizing experimental colitis induction at the RAGE (receptor for advanced glycation end pro- and progression. Body weight, presence of gross blood in ducts) site only in micromolar concentrations [11,13-15] the feces and stool consistency were recorded daily and such interaction leads to mitogen-activated protein (from day 0 to 7) by an observer blinded to the treat- kinase (MAPK) phosphorylation and consequent nuclear ment. According to the criteria proposed by Cooper factor-kappaB (NF-κB) activation, which, in turn, promote et al. [19], the DAI was determined by scoring changes the transcription of different cytokines and inducible nitric in: weight loss (0 = none; 1 = 1 to 5%; 2 = 5 to 10%; 3 = oxide synthase (iNOS) protein [14]. Molecular targeting of 10 to 20%; 4 = >20%); stool consistency (0 = normal; 2 = S100B protein during intestinal inflammation might there- loose; 4 = diarrhea) and rectal bleeding (0 = normal; 2 = fore represent an innovative approach to treat UC. occult bleeding; 4 = gross bleeding). At the end of the Pentamidine isethionate, discovered to have antiproto- experiment, mice were sacrificed and colons and spleens zoal activity in 1938, and approved in the United States were isolated to measure the length and weight of colon for the treatment of Pneumocystis carinii pneumonia and spleen, respectively. and other protozoal diseases [16], appears to be an in- triguing candidate. In addition to its antiprotozoal activ- Preparation of cytosolic extracts and western blot ity, pentamidine has been reported to inhibit S100B analysis activity because of its ability to block the interaction at Removed colonic tissues were processed for western blot the Ca++/p53 site of the protein [17]. analysis. Briefly, after homogenization in ice-cold hypo- Based on this background, the present study was tonic lysis buffer, protein concentration was determined aimed at evaluating the beneficial effect of a daily ad- using Bio-Rad protein assay kit (Bio-Rad, Milan, Italy). ministration of pentamidine in an acute model of UC Analysis of cyclooxigenase (COX)-2, iNOS, TNF-α, S100B, induced by dextran sulphate sodium (DSS) administra- glial fibrillary acidic protein (GFAP), phosphorylated-p38 tion in drinking water in CD-1 mice. DSS-induced colitis (p-p38) MAPK, p50, p65 and β-actin protein expression is highly reproducible and is a well-known in vivo model was performed on total protein fractions of homogenates. of experimental colitis in rodents that reproduces many Equivalent amounts (50 μg) of each homogenate under- features of UC [18]. We tested the effect of pentamidine went electrophoresis through a polyacrilamide minigel. on (i) intensity of the symptoms (diarrhea, blood in the Proteins were then transferred onto nitrocellulose mem- feces, animal weight loss) through a disease activity index brane that were saturated by incubation with 10% nonfat (DAI) scale [19]; (ii) release of cytokines and proinflamma- dry milk in 1× PBS overnight at 4°C and then incubated tory signaling molecules present in mice plasma; (iii) post- with either mouse anti-S100B (1:200 v/v, Neo-Marker, mortem evaluation of macroscopic shortening of large Milan, Italy), mouse anti-iNOS (1:2000 v/v, BD Bios- intestine and spleen weight; (iv) global colonic inflamma- ciences, Milan, Italy), rabbit anti-COX-2 (1:250 v/v, BD tion by the evaluation of biochemical and histological Biosciences), GFAP (1:5000 v/v, Abcam, Cambridge, UK), changes of the tissue. mouse anti-p50, mouse anti-p65 (1:1000 v/v, Santa Cruz Biotechnology, Santa Cruz, CA, USA), or mouse anti-β- Methods actin (1:1,000 v/v, Santa Cruz Biotechnology) for 2 h at Animals and experimental design room temperature (RT). Membranes were then incubated Six-weeks-old male CD-1 mice (25 to 35 g; Harlan La- with anti-mouse or anti-rabbit immunoglobulins coupled boratories, Udine, Italy) were used for the experiments. to peroxidase (1:2000 v/v, Dako, Milan, Italy). Immune Animals were randomly divided into five groups (n = 10 complexes were revealed by using enhanced chemilumin- each): noncolitic control group; colitic group; colitic escence detection reagents (Amersham Biosciences, Milan, group receiving daily pentamidine 0.8 mg/kg; colitic group Italy) and exposed to Kodak X-Omat film (Eastman Kodak receiving daily pentamidine 4 mg/kg; noncolitic group Co., Rochester, NY, USA OK). Protein bands were then receiving daily pentamidine 4 mg/kg (as drug internal scanned and densitometrically analyzed with a GS-700 im- control). Colitis was induced by administrating DSS aging densitometer. (4% w/v, MW 36,000 to 50,000) in drinking water for six consecutive days (starting from day 1), as described in Figure 1A. Pentamidine was given intraperitoneally Preparation of blood samples starting at day 2 through day 6. At day 7, animals were Before being
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